DARZALEX 20 mg/mL concentrate for solution for infusion.

The Summary of Product Characteristics (SPC or SmPC) is a specific document, the wording of which has been agreed with the regulatory authority as part of the medicine approval process. It is required before any medicine is allowed on the market in Europe. It is designed to assist doctors and pharmacists in prescribing and supplying the product.

Summary of Product Characteristics last updated on medicines.ie: 22/4/2020

This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.

When a pharmaceutical company changes any document, a new version is published on medicines.ie. For each version, we show the dates it was published on medicines.ie and the reasons for change.

Updated on 22 April 2020 SmPC

Reasons for updating

Change to section 5.1 - Pharmacodynamic properties

Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

5.1 Pharmacodynamic properties

………….

A total of 706 patients were randomised: 350 to the D-VMP arm and 356 to the VMP arm. The baseline demographic and disease characteristics were similar between the two treatment groups. The median age was 71 (range: 40-93) years, with 30% of the patients ≥75 years of age. The majority were white (85%), female (54%), 25% had an ECOG performance score of 0, 50% had an ECOG performance score of 1 and 25% had an ECOG performance score of 2. Patients had IgG/IgA/Light chain myeloma in 64%/22%/10% of instances, 19% had ISS Stage I, 42% had ISS Stage II, 38% had ISS Stage III disease and 84% had standard risk cytogenetics. Efficacy was evaluated by PFS based on IMWG criteria and overall survival (OS).

With a median follow‑up of 16.5months, Tthe primary analysis of PFS in Study MMY3007 showed an improvement in the D-VMP arm as compared to the VMP arm; the median PFS had not been reached in the D-VMP arm and was 18.1 months in the VMP arm (HR=0.5; 95% CI: 0.38, 0.65; p<0.0001)., representing 50% reduction in the risk of disease progression or death in patients treated with D-VMP. Results of an updated PFS analysis approximately 4 months after the original clinical cutoff, continued to show an improvement in PFS for patients in the D-VMP arm compared with the VMP arm. Median PFS was not reached in the D-VMP arm and was 19.3 months in the VMP arm (HR=0.46; 95% CI: 0.36, 0.60; p<0.0001). Results of an updated PFS analysis after a median follow‑up of 40 months continued to show an improvement in PFS for patients in the D‑VMP arm compared with the VMP arm. Median PFS was 36.4 months in the D‑VMP arm and 19.3 months in the VMP arm (HR=0.42; 95% CI: 0.34, 0.51; p<0.0001), representing a 58% reduction in the risk of disease progression or death in patients treated with D‑VMP.

After a median follow‑up of 40 months, D‑VMP has shown an overall survival (OS) advantage over the VMP arm (HR=0.60; 95% CI: 0.46, 0.80; p=0.0003), representing a 40% reduction in the risk of death in patients treated in the D‑VMP arm. Median OS was not reached for either arm.

……………………

With a median follow‑up of 13.5 months, the primary analysis of PFS in Sstudy MMY3003 demonstrated an improvement in PFS in the DRd arm as compared to the Rd arm; the median PFS had not been reached in the DRd arm and was 18.4 months in the Rd arm (HR=0.37; 95% CI: 0.27, 0.52; p<0.0001)., representing 63% reduction in the risk of disease progression or death in patients treated with DRd Results of an updated PFS analysis after a median follow‑up of 55 months continued to show an improvement in PFS for patients in the DRd arm compared with the Rd arm. Median PFS was 45.0 months in the DRd arm and 17.5 months in the Rd arm (HR=0.44; 95% CI: 0.35, 0.54; p<0.0001), representing a 56% reduction in the risk of disease progression or death in patients treated with DRd (see Figure 34).

cA Chi-Squared Mantel‑Haenszel estimate of the common odds ratio is used. An odds ratio >1 indicates an advantage for DRd.

dp-value is from a likelihood-ratio Chi-SquaredFisher’s exact test.

………….

With a median follow‑up of 7.4 months, the primary analysis of PFS inSstudy MMY3004 demonstrated an improvement in PFS in the DVd arm as compared to the Vd arm; the median PFS had not been reached in the DVd arm and was 7.2 months in the Vd arm (HR [95% CI]: 0.39 [0.28, 0.53]; p-value<0.0001), representing a 61% reduction in the risk of disease progression or death for patients treated with DVd versus Vd. Results of an updated PFS analysis after a median follow‑up of 50 months continued to show an improvement in PFS for patients in the DVd arm compared with the Vd arm. Median PFS was 16.7 months in the DVd arm and 7.1 months in the Vd arm (HR [95% CI]: 0.31 [0.24, 0.39]; p-value<0.0001), representing a 69% reduction in the risk of disease progression or death in patients treated with DVd versus Vd(see Figure 45).

cA Chi-Squared Mantel-Haenszel estimate of the common odds ratio is used. An odds ratio >1 indicates an advantage for DVd.

dp-value is from a likelihood-ratio chi-squaredFisher’s exact test.

Updated on 22 January 2020 SmPC

Reasons for updating

Change to section 4.1 - Therapeutic indications

Change to section 4.2 - Posology and method of administration

Change to section 4.8 - Undesirable effects

Change to section 5.1 - Pharmacodynamic properties

Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

4.1 Therapeutic indications

DARZALEX is indicated:

in combination with lenalidomide and dexamethasone or with bortezomib, melphalan and prednisone for the treatment of adult patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplant.

in combination with bortezomib, thalidomide and dexamethasone for the treatment of adult patients with newly diagnosed multiple myeloma who are eligible for autologous stem cell transplant.

in combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, for the treatment of adult patients with multiple myeloma who have received at least one prior therapy.

as monotherapy for the treatment of adult patients with relapsed and refractory multiple myeloma, whose prior therapy included a proteasome inhibitor and an immunomodulatory agent and who have demonstrated disease progression on the last therapy.4.2 Posology and method of administrationDosing schedule in combination with bortezomib, thalidomide and dexamethasone (4-week cycle regimens) for treatment of newly diagnosed patients eligible for autologous stem cell transplant (ASCT):

The recommended dose is DARZALEX 16 mg/kg body weight administered as an intravenous infusion according to the following dosing schedule in Table 3.

Table 5 6 summarises the adverse drug reactions that occurred in patients receiving DARZALEX. The data reflects exposure to DARZALEX (16 mg/kg) in 1530 2066 patients with multiple myeloma including 1374 1910 patients who received DARZALEX in combination with background regimens and 156 patients who received DARZALEX as monotherapy. Post‑marketing adverse reactions are also included.

In Study MMY3006, the number of CD34+ cell yield was numerically lower in the D-VTd arm compared with the VTd arm (Median: D-VTd: 6.3x106/kg; VTd 8.9x106/kg) and among those who completed mobilization, more patients in the D-VTd group received plerixafor compared to those in the VTd arm (D-VTd: 21.7%; VTd: 7.9%). The rates of engraftment and haematopoietic reconstitution was similar among the transplanted subjects in the D-VTd and VTd arms (D-VTd: 99.8%; VTd: 99.6%; as measured by the recovery of neutrophils > 0.5x109/L, leukocytes > 1.0x109/L, and platelets > 50x109/L without transfusion).

Frequencies are defined as very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000) and very rare (< 1/10,000). Within each frequency grouping, where relevant, adverse reactions are presented in order of decreasing seriousness.

cInfusion-related reaction includes terms determined by investigators to be related to infusion, see below

Infusion‑related reactions

In clinical trials…….. vomiting and nausea (see section 4.4).

When DARZALEX dosing was interrupted in the setting of ASCT (Study MMY3006) for a median of 3.75 (range: 2.4; 6.9) months, upon re-initiation of DARZALEX the incidence of IRRs was 11% at first infusion following ASCT. Infusion rate/dilution volume used upon re-initiation was that used for the last DARZALEX infusion prior to interruption due to ASCT. IRRs occurring at re-initiation of DARZALEX following ASCT were consistent in terms of symptoms and severity (Grade 3/4:<1%) with those reported in previous studies at Week 2 or subsequent infusions.

Pneumonia was the most commonly reported severe (Grade 3 or 4) infection across studies. In the active controlled studies, discontinuations from treatment due to infections (1-4%) and fatal infections were generally infrequent and balanced between the DARZALEX containing regimens and active control arms. Fatal infections were primarily due to pneumonia and sepsis.

Study MMY3006 is a 2 Part, open-label, randomized, active-controlled Phase 3 study.Part 1 compared induction and consolidation treatment with DARZALEX 16 mg/kg in combination with bortezomib, thalidomide and dexamethasone (D-VTd) to treatment with bortezomib, thalidomide and dexamethasone (VTd) in patients with newly diagnosed multiple myeloma eligible for ASCT.The consolidation phase of treatment began a minimum of 30 days post-ASCT, when the patient had recovered sufficiently, and engraftment was complete. In Part 2, subjects with at least a partial response (PR) by Day 100 post-transplant were re-randomized in a 1:1 ratio to daratumumab maintenance or observation only. Only results from Part 1 are described henceforth.

Bortezomib was administered by SC injection or IV injection at a dose of 1.3 mg/m2 body surface area twice weekly for two weeks (Days 1, 4, 8, and 11) of repeated 28 day (4-week) induction treatment cycles (Cycles 1-4) and two consolidation cycles (Cycles 5 and 6) following ASCT after Cycle 4. Thalidomide was administered orally at 100 mg daily during the six bortezomib cycles. Dexamethasone (oral or intravenous) was administered at 40 mg on Days 1, 2, 8, 9, 15, 16, 22 and 23 of Cycles 1 and 2, and at 40 mg on Days 1-2 and 20 mg on subsequent dosing days (Days 8, 9, 15, 16) of Cycles 3-4. Dexamethasone 20 mg was administered on Days 1, 2, 8, 9, 15, 16 in Cycles 5 and 6. On the days of DARZALEX infusion, the dexamethasone dose was administered intravenously as a pre-infusion medication. Dose adjustments for bortezomib, thalidomide and dexamethasone were applied according to manufacturer’s prescribing information.

A total of 1085 patients were randomized: 543 to the D-VTd arm and 542 to the VTd arm. The baseline demographic and disease characteristics were similar between the two treatment groups. The median age was 58 (range: 22 to 65) years. All patients were ≤ 65 years: 43% were in the age group ≥ 60-65 years, 41% were in the age group ≥ 50-60 years and 16% below age of 50 years. The majority were male (59%), 48% had an ECOG performance score of 0, 42% had an ECOG performance score of 1 and 10% had an ECOG performance score of 2. Forty percent had International Staging System (ISS) Stage I, 45% had ISS Stage II and 15% had ISS Stage III disease.

eMantel-Haenszel estimate of the common odds ratio for stratified tables is used.

Results of aPFS analysis by censoring patients who were randomized to daratumumab maintenance in the second randomization, at the date of the second randomization showed HR=0.50; 95% CI: 0.34, 0.75; p=0.0005.

4.1 Therapeutic indications

DARZALEX is indicated:

in combination with lenalidomide and dexamethasone or with bortezomib, melphalan and prednisone for the treatment of adult patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplant.

in combination with bortezomib, thalidomide and dexamethasone for the treatment of adult patients with newly diagnosed multiple myeloma who are eligible for autologous stem cell transplant.

in combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, for the treatment of adult patients with multiple myeloma who have received at least one prior therapy.

as monotherapy for the treatment of adult patients with relapsed and refractory multiple myeloma, whose prior therapy included a proteasome inhibitor and an immunomodulatory agent and who have demonstrated disease progression on the last therapy.4.2 Posology and method of administrationDosing schedule in combination with bortezomib, thalidomide and dexamethasone (4-week cycle regimens) for treatment of newly diagnosed patients eligible for autologous stem cell transplant (ASCT):

The recommended dose is DARZALEX 16 mg/kg body weight administered as an intravenous infusion according to the following dosing schedule in Table 3.

Table 5 6 summarises the adverse drug reactions that occurred in patients receiving DARZALEX. The data reflects exposure to DARZALEX (16 mg/kg) in 1530 2066 patients with multiple myeloma including 1374 1910 patients who received DARZALEX in combination with background regimens and 156 patients who received DARZALEX as monotherapy. Post‑marketing adverse reactions are also included.

In Study MMY3006, the number of CD34+ cell yield was numerically lower in the D-VTd arm compared with the VTd arm (Median: D-VTd: 6.3x106/kg; VTd 8.9x106/kg) and among those who completed mobilization, more patients in the D-VTd group received plerixafor compared to those in the VTd arm (D-VTd: 21.7%; VTd: 7.9%). The rates of engraftment and haematopoietic reconstitution was similar among the transplanted subjects in the D-VTd and VTd arms (D-VTd: 99.8%; VTd: 99.6%; as measured by the recovery of neutrophils > 0.5x109/L, leukocytes > 1.0x109/L, and platelets > 50x109/L without transfusion).

Frequencies are defined as very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000) and very rare (< 1/10,000). Within each frequency grouping, where relevant, adverse reactions are presented in order of decreasing seriousness.

cInfusion-related reaction includes terms determined by investigators to be related to infusion, see below

Infusion‑related reactions

In clinical trials…….. vomiting and nausea (see section 4.4).

When DARZALEX dosing was interrupted in the setting of ASCT (Study MMY3006) for a median of 3.75 (range: 2.4; 6.9) months, upon re-initiation of DARZALEX the incidence of IRRs was 11% at first infusion following ASCT. Infusion rate/dilution volume used upon re-initiation was that used for the last DARZALEX infusion prior to interruption due to ASCT. IRRs occurring at re-initiation of DARZALEX following ASCT were consistent in terms of symptoms and severity (Grade 3/4:<1%) with those reported in previous studies at Week 2 or subsequent infusions.

Pneumonia was the most commonly reported severe (Grade 3 or 4) infection across studies. In the active controlled studies, discontinuations from treatment due to infections (1-4%) and fatal infections were generally infrequent and balanced between the DARZALEX containing regimens and active control arms. Fatal infections were primarily due to pneumonia and sepsis.

Study MMY3006 is a 2 Part, open-label, randomized, active-controlled Phase 3 study.Part 1 compared induction and consolidation treatment with DARZALEX 16 mg/kg in combination with bortezomib, thalidomide and dexamethasone (D-VTd) to treatment with bortezomib, thalidomide and dexamethasone (VTd) in patients with newly diagnosed multiple myeloma eligible for ASCT.The consolidation phase of treatment began a minimum of 30 days post-ASCT, when the patient had recovered sufficiently, and engraftment was complete. In Part 2, subjects with at least a partial response (PR) by Day 100 post-transplant were re-randomized in a 1:1 ratio to daratumumab maintenance or observation only. Only results from Part 1 are described henceforth.

Bortezomib was administered by SC injection or IV injection at a dose of 1.3 mg/m2 body surface area twice weekly for two weeks (Days 1, 4, 8, and 11) of repeated 28 day (4-week) induction treatment cycles (Cycles 1-4) and two consolidation cycles (Cycles 5 and 6) following ASCT after Cycle 4. Thalidomide was administered orally at 100 mg daily during the six bortezomib cycles. Dexamethasone (oral or intravenous) was administered at 40 mg on Days 1, 2, 8, 9, 15, 16, 22 and 23 of Cycles 1 and 2, and at 40 mg on Days 1-2 and 20 mg on subsequent dosing days (Days 8, 9, 15, 16) of Cycles 3-4. Dexamethasone 20 mg was administered on Days 1, 2, 8, 9, 15, 16 in Cycles 5 and 6. On the days of DARZALEX infusion, the dexamethasone dose was administered intravenously as a pre-infusion medication. Dose adjustments for bortezomib, thalidomide and dexamethasone were applied according to manufacturer’s prescribing information.

A total of 1085 patients were randomized: 543 to the D-VTd arm and 542 to the VTd arm. The baseline demographic and disease characteristics were similar between the two treatment groups. The median age was 58 (range: 22 to 65) years. All patients were ≤ 65 years: 43% were in the age group ≥ 60-65 years, 41% were in the age group ≥ 50-60 years and 16% below age of 50 years. The majority were male (59%), 48% had an ECOG performance score of 0, 42% had an ECOG performance score of 1 and 10% had an ECOG performance score of 2. Forty percent had International Staging System (ISS) Stage I, 45% had ISS Stage II and 15% had ISS Stage III disease.

eMantel-Haenszel estimate of the common odds ratio for stratified tables is used.

Results of aPFS analysis by censoring patients who were randomized to daratumumab maintenance in the second randomization, at the date of the second randomization showed HR=0.50; 95% CI: 0.34, 0.75; p=0.0005.

Updated on 22 January 2020 PIL

Reasons for updating

Change to section 4 - possible side effects

Change to section 6 - date of revision

Updated on 20 November 2019 PIL

Reasons for updating

Change to section 4 - possible side effects

Change to section 6 - date of revision

Updated on 20 November 2019 SmPC

Reasons for updating

Change to section 4.1 - Therapeutic indications

Change to section 4.2 - Posology and method of administration

Change to section 4.5 - Interaction with other medicinal products and other forms of interaction

Change to section 4.8 - Undesirable effects

Change to section 5.1 - Pharmacodynamic properties

Change to section 5.2 - Pharmacokinetic properties

Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

4.1 Therapeutic indications

DARZALEX is indicated:

in combination with lenalidomide and dexamethasone or with bortezomib, melphalan and prednisone for the treatment of adult patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplant.

as monotherapy for the treatment of adult patients with relapsed and refractory multiple myeloma, whose prior therapy included a proteasome inhibitor and an immunomodulatory agent and who have demonstrated disease progression on the last therapy.

in combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, for the treatment of adult patients with multiple myeloma who have received at least one prior therapy.

as monotherapy for the treatment of adult patients with relapsed and refractory multiple myeloma, whose prior therapy included a proteasome inhibitor and an immunomodulatory agent and who have demonstrated disease progression on the last therapy.

4.2 Posology and method of administration

DARZALEX should be administered by a healthcare professional, in an environment where resuscitation facilities are available.

Pre‑ and post‑infusion medications should be administered to reduce the risk of infusion‑related reactions (IRRs) with daratumumab. See below “Recommended concomitant medications”, “Management of infusion‑related reactions” and section 4.4.

Posology

Dosing schedule in combination with lenalidomide (4‑week cycle regimen) and for monotherapy:

The recommended dose is DARZALEX 16 mg/kg body weight administered as an intravenous infusion according to the following dosing schedule in Table 1.

Bortezomib is given twice weekly at Weeks 1, 2, 4 and 5 for the first 6-week cycle, followed by once weekly at Weeks 1, 2, 4 and 5 for eight more 6-week cycles. For information on the VMP dose and dosing schedule when administered with DARZALEX, see section 5.1.

Relapsed/Refractory multiple myeloma

Dosing schedule for monotherapy and in combination with lenalidomide (4‑week cycle regimen):

The recommended dose is DARZALEX 16 mg/kg body weight administered as an intravenous infusion according to the following dosing schedule in Table 2.

Table 5 summarises the adverse drug reactions that occurred in patients receiving DARZALEX. The data reflects exposure to DARZALEX (16 mg/kg) in1530 patients with multiple myeloma including 1374 patients who received DARZALEX in combination with background regimens and 156 patients who received DARZALEX as monotherapy 1166 patients with multiple myeloma including 872 patients from three Phase III active-controlled trials who received DARZALEX in combination with either lenalidomide and dexamethasone (DRd; n=283; Study MMY3003), bortezomib and dexamethasone (DVd; n=243; Study MMY3004), or bortezomib, melphalan and prednisone (D‑VMP, n=346; Study MMY3007), and five open-label, clinical trials in which patients received DARZALEX either in combination with pomalidomide and dexamethasone (DPd; n=103), in combination with lenalidomide and dexamethasone (n=35) or as monotherapy (n=156). Post‑marketing adverse reactions are also included.

cInfusion-related reaction includes terms determined by investigators to be related to infusion, see below

Infusion‑related reactions

In clinical trials (monotherapy and combination treatments; N=11661530) the incidence of any grade infusion‑related reactions was 40% with the first (16 mg/kg, Week 1) infusion of DARZALEX, 2% with the Week 2 infusion, and cumulatively 4% with subsequent infusions. Less than 1% of patients had a Grade 3/4 infusion‑related reaction with the Week 2 or subsequent infusions. Grade 4 infusion reactions were reported in 2/1166 (0.2%) of patients.

The median time to onset of a reaction was 1.4 5 hours (range: 0 to 72.8 hours). The incidence of infusion modifications due to reactions was 37%. Median durations of 16 mg/kg infusions for the 1st Week, 2nd Week and subsequent infusions were approximately 7, 4.3 and 3.4 hours respectively.

Pneumonia was the most commonly reported severe (Grade 3 or 4) infection across studies. In the active controlled studies, discontinuations from treatment due to infections (1-4%) Discontinuations from treatment due to infections were reported in 1% to 5% of patients. Fand fatal infections were generally infrequent and balanced between the DARZALEX containing regimens and active control arms.(<2%) in the controlled studies andFatal infections were primarily due to pneumonia and sepsis

5.1 Pharmacodynamic properties

Immunogenicity

Patients treated with daratumumab monotherapy (n=199) and combination therapy (n=412750) were evaluated for anti‑therapeutic antibody responses to daratumumab at multiple time points during treatment and up to 8 weeks following the end of treatment. Following the start of daratumumab treatment, none of the monotherapy patients and 2 of the 412 750 combination therapy patients tested.

Study MMY3008, an open-label, randomized, active-controlled Phase III study, compared treatment with DARZALEX 16 mg/kg in combination with lenalidomide and low-dose dexamethasone (DRd) to treatment with lenalidomide and low-dose dexamethasone (Rd) in patients with newly diagnosed multiple myeloma. Lenalidomide (25 mg once daily orally on Days 1-21 of repeated 28-day [4-week] cycles) was given with low dose oral or intravenous dexamethasone 40 mg/week (or a reduced dose of 20 mg/week for patients >75 years or body mass index [BMI] <18.5). On DARZALEX infusion days, the dexamethasone dose was given as a pre-infusion medication. Dose adjustments for lenalidomide and dexamethasone were applied according to manufacturer’s prescribing information. Treatment was continued in both arms until disease progression or unacceptable toxicity.

A total of 737 patients were randomized: 368 to the DRd arm and 369 to the Rd arm. The baseline demographic and disease characteristics were similar between the two treatment groups. The median age was 73 (range: 45-90) years, with 44% of the patients ≥75 years of age. The majority were white (92%), male (52%), 34% had an Eastern Cooperative Oncology Group (ECOG) performance score of 0, 49.5% had an ECOG performance score of 1 and 17% had an ECOG performance score of ≥2. Twenty-seven percent had International Staging System (ISS) Stage I, 43% had ISS Stage II and 29% had ISS Stage III disease. Efficacy was evaluated by progression free survival (PFS) based on International Myeloma Working Group (IMWG) criteria.

Study MMY3008 showed an improvement in Progression Free Survival (PFS) in the DRd arm as compared to the Rd arm; the median PFS had not been reached in the DRd arm and was 31.9 months in the Rd arm (hazard ratio [HR]=0.56; 95% CI: 0.43, 0.73; p<0.0001), representing 44% reduction in the risk of disease progression or death in patients treated with DRd.Results of an updated PFS analysis approximately 9months after the original clinical cutoff, continued to show an improvement in PFS for patients in the DRd arm compared with the Rd arm. Median PFS was not reached in the DRd arm and was 33.8 months in the Rd arm (HR=0.56; 95% CI: 0.44, 0.71; p<0.0001).

d Mantel-Haenszel estimate of the odds ratio for un-stratified tables is used. An odds ratio > 1 indicates an advantage for DRd.

e p-value from Fisherʼs exact test.

In responders, the median time to response was 1.05 months (range: 0.2 to 12.1 months) in the DRd group and 1.05 months (range: 0.3 to 15.3 months) in the Rd group. The median duration of response had not been reached in the DRd group and was 34.7 months (95% CI: 30.8, not estimable) in the Rd group.

5.2 Pharmacokinetic properties

Three Four population PK analyses were performed to describe the PK characteristics of daratumumab and to evaluate the influence of covariates on the disposition of daratumumab in patients with multiple myeloma; Analysis 1 (n=223) in patients receiving DARZALEX monotherapy while Analysis 2 (n=694), and Analysis 3 (n=352) and Analysis 4 (n=355) were conducted in patients with multiple myeloma that received daratumumab combination therapies. Analysis 2 included 694 patients (n=326 for lenalidomide-dexamethasone; n=246 for bortezomib-dexamethasone; n=99 for pomalidomide-dexamethasone; n=11 for bortezomib-melphalan-prednisone; and n=12 for bortezomib-thalidomide-dexamethasone), and Analysis 3 included 352 patients (bortezomib‑melphalan‑prednisone) and Analysis 4 included 355 patients (lenalidomide-dexamethasone).

Two Three additional population PK analyses (Analysis 2 and, Analysis 3 and Analysis 4) were conducted in patients with multiple myeloma that received daratumumab combination therapies. Daratumumab concentration‑time profiles were similar following the monotherapy and combination therapies. The mean estimated terminal half-life associated with linear clearance in combination therapy was approximately 2215‑23 days.

Based on the three four population PK analyses (Analyses 1-34) body weight was identified as a statistically significant covariate for daratumumab clearance. Therefore, body weight based dosing is an appropriate dosing strategy for the multiple myeloma patients.

Special populations

Age and gender

Based on three four individual population PK analyses (1-34) in patients receiving daratumumab monotherapy or various combination therapies (Analyses 1-34), age (range: 31‑93 years) had no clinically important effect on the PK of daratumumab, and the exposure of daratumumab was similar between younger (aged <65 years, n=515518) and older (aged ≥65 to <75 years n=562761; aged ≥75 years, n=181334) patients.

……

Renal impairment

No formal studies of daratumumab in patients with renal impairment have been conducted. Three Four individual population PK analyses were performed based on pre‑existing renal function data in patients receiving daratumumab monotherapy, or various combination therapies (Analyses 1-34), and included a total of 381 441 patients with normal renal function (creatinine clearance [CRCL] ≥90 mL/min), 480 621 with mild renal impairment (CRCL <90 and ≥60 mL/min), 376 523 with moderate renal impairment (CRCL <60 and ≥30 mL/min), and 20 27 with severe renal impairment or end stage renal disease (CRCL<30 mL/min). No clinically important differences in exposure to daratumumab were observed between patients with renal impairment and those with normal renal function.

Hepatic impairment

No formal studies of daratumumab in patients with hepatic impairment have been conducted. Changes in hepatic function are unlikely to have any effect on the elimination of daratumumab since IgG1 molecules such as daratumumab are not metabolised through hepatic pathways.

Three Four individual population PK analyses were performed in patients receiving daratumumab monotherapy or various combination therapies (Analyses 1-34), and included a total of 1081 1404 patients with normal hepatic function (total bilirubin [TB] and aspartate aminotransferase [AST] ≤ upper limit of normal [ULN]), 159 189 with mild hepatic impairment (TB 1.0 x to 1.5 x ULN or AST >ULN) and 7 8 patients with moderate (TB > 1.5 x to 3.0 x ULN; n=67), or severe (TB > 3.0 x ULN; n=1) hepatic impairment. No clinically important differences in the exposure to daratumumab were observed between patients with hepatic impairment and those with normal hepatic function.

Race

Based on three four individual population PK analyses in patients receiving either daratumumab monotherapy or various combination therapies (Analyses 1-34), the exposure to daratumumab was similar between white (n=10461371) and non‑white subjects (n=212242).

Updated on 2 July 2019 PIL

Reasons for updating

Change to section 2 - what you need to know - warnings and precautions

Change to section 4 - possible side effects

Change to section 6 - date of revision

Updated on 2 July 2019 SmPC

Reasons for updating

Change to section 4.4 - Special warnings and precautions for use

Change to section 4.8 - Undesirable effects

Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

4.4 Special warnings and precautions for use

Hepatitis B virus (HBV) Reactivation

Hepatitis B virus reactivation, in some cases fatal, has been reported in patients treated with DARZALEX. HBV screening should be performed in all patients before initiation of treatment with DARZALEX.

For patients with evidence of positive HBV serology, monitor for clinical and laboratory signs of HBV reactivation during, and for at least six months following the end of DARZALEX treatment. Manage patients according to current clinical guidelines. Consider consulting a hepatitis disease expert as clinically indicated.

In patients who develop reactivation of HBV while on DARZALEX, suspend treatment with DARZALEX and institute appropriate treatment. Resumption of DARZALEX treatment in patients whose HBV reactivation is adequately controlled should be discussed with physicians with expertise in managing HBV.

4.8 Undesirable effects

Infections and infestations

Pneumoniaa

Very Common

16

11

Upper respiratory tract infectiona

50

5

Influenza

Common

4

1*

Hepatitis B Virus reactivationb

Uncommon

-

-

Updated on 21 December 2018 PIL

Reasons for updating

Change to section 3 - dose and frequency

Change to section 6 - date of revision

Updated on 21 December 2018 SmPC

Reasons for updating

Change to section 4.2 - Posology and method of administration

Change to section 4.8 - Undesirable effects

Change to section 5.2 - Pharmacokinetic properties

Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

Updated on 10 December 2018 PIL

Reasons for updating

Change to section 6 - what the product looks like and pack contents

Change to section 6 - date of revision

Updated on 10 December 2018 SmPC

Reasons for updating

Change to section 6.5 - Nature and contents of container

Change to section 8 - Marketing authorisation number(s)

Change to section 10 - Date of revision of the text

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6.5 Nature and contents of container

5 mL concentrate in a Type 1 glass vial with an elastomeric closure and an aluminium seal with a flip‑off button containing 100 mg of daratumumab. Pack size of 1 vial.

20 mL concentrate in a Type 1 glass vial with an elastomeric closure and an aluminium seal with a flip‑off button containing 400 mg of daratumumab. Pack size of 1 vial.

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Addition 4.2 Posology and method of administrationof a new indication.

DARZALEX is indicated:

in combination with bortezomib, melphalan and prednisone for the treatment of adult patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplant.

4.2 Posology and method of administration

This section has been extensively revised

Section 4.8

Added. very common , hu ypertension Common: pulmonary oedema

Section 5.1 and 5.2 updated

Updated on 28 June 2018 SmPC

Reasons for updating

Change to section 4.4 - Special warnings and precautions for use

Change to section 4.8 - Undesirable effects

Change to section 10 - Date of revision of the text

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Unforunately the is section will not allow all the changes to be published. Please conatc Janssen-Cilag Ltd medical informatiomn if you would like the details of the changes

Updated on 28 June 2018 PIL

Reasons for updating

Change to section 2 - what you need to know - warnings and precautions

Change to section 4 - possible side effects

Change to section 6 - date of revision

Change to information for healthcare professionals

Updated on 16 May 2018 SmPC

Reasons for updating

Change to section 4.5 - Interaction with other medicinal products and other forms of interaction

Change to section 10 - Date of revision of the text

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Updated on 16 August 2017 PIL

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Change to section 6.3 - Shelf life

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6.3 Shelf life

Unopened vials

18 24 months

Updated on 16 August 2017 SmPC

Reasons for updating

New SmPC for new product

Legal category: Product subject to medical prescription which may not be renewed (A)

Updated on 16 August 2017 SmPC

Reasons for updating

Change to section 6.3 - Shelf life

Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

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6.3 Shelf life

Unopened vials

18 24 months

Updated on 3 May 2017 SmPC

Reasons for updating

Change to section 4.1 - Therapeutic indications

Change to section 4.2 - Posology and method of administration

Change to section 4.4 - Special warnings and precautions for use

Change to section 4.5 - Interaction with other medicinal products and other forms of interaction

Change to section 4.8 - Undesirable effects

Change to section 5.1 - Pharmacodynamic properties

Change to section 5.2 - Pharmacokinetic properties

Change to section 10 - Date of revision of the text

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4.1 Therapeutic indications

DARZALEX is indicated:

·as monotherapy is indicated for the treatment of adult patients with relapsed and refractory multiple myeloma, whose prior therapy included a proteasome inhibitor and an immunomodulatory agent and who have demonstrated disease progression on the last therapy.

·in combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone,for the treatment of adult patients with multiple myeloma who have received at least one prior therapy

4.2 Posology and method of administration

Dose

Standard dosing for monotherapy and in combination with lenalidomide (4‑week cycle regimen):

The recommended dose is DARZALEX 16 mg/kg body weight administered as an intravenous infusion according to the following dosing schedule in Table1.:

For dose and schedule of medicinal products administeredwith DARZALEX, see section5.1 and the corresponding Summary of Product Characteristics.

Infusion rates

Following dilution the DARZALEX infusion should be intravenously administered at the appropriate initial infusion rate, as presented in Table 2 3 below. Incremental escalation of the infusion rate should be considered only if the previous infusion of daratumumab was well‑toleratedin the absence of infusion reactions. as defined in Table 2.

Table 32: Infusion rates for DARZALEX administration

Dilution volume

Initial infusion rate (first hour)

Increments of infusion ratea

Maximum infusion rate

First infusion

1,000 mL

50 mL/hour

50 mL/hour every hour

200 mL/hour

Second infusionainfusionb

500 mL

50 mL/hour

50 mL/hour every hour

200 mL/hour

Subsequent infusionsbinfusionsc

500 mL

100 mL/hour

50 mL/hour every hour

200 mL/hour

aIncremental escalation of the infusion rate should be considered only in the absence of infusion reactions.

abA dilution volume of 500mL should be used only if there were no ≥ Grade 1 IRRs during the first 3 hours of the first infusion. Otherwise, continue to use a dilution volume of 1000mL and instructions for the first infusion.Modified rates should only be used if the first infusion of DARZALEX was well‑tolerated as defined by an absence of ≥ Grade 1 IRRs during the first 3 hours.

bcA modified initial rate for subsequent infusions (i.e. third infusion onwards) should only be used only if there were no ≥ Grade 1 IRRs during a final infusion rate of ≥ 100 mL/hr in the first two infusions. Otherwise, use instructions for the second infusionModified rates should only be used if the first 2 infusions of DARZALEX were well‑tolerated as defined by an absence of ≥ Grade 1 IRRs during a final infusion rate of ≥ 100 mL/hr.

Management of infusion‑related reactions

Management of IRRs may further require reduction in the rate of infusion, or treatment discontinuation of DARZALEX as outlined below (see section 4.4).

·Grade 1‑2 (mild to moderate): Once the patient’s condition is stablereaction symptoms resolve, the infusion should be resumed at no more than half the rate at which the IRR occurred. If the patient does not experience any further IRR symptoms, infusion rate escalation may be resumed at increments and intervals as clinically appropriate up to the maximum rate of 200mL/hour (Table 23).

·Grade 3 (severe): If the intensity of the IRR decreases to Grade 2 or lowerOnce reaction symptoms resolve, restarting of the infusion may be considered at no more than half the rate at which the reaction occurred. If the patient does not experience additional symptoms, infusion rate escalation may be resumed at increments and intervals as appropriate (Table 32). The procedure above should be repeated in the event of recurrence of Grade 3 symptoms. Permanently discontinue DARZALEXupon the third occurrence of a Grade 3 or greater infusion reaction if the patient experiences a ≥ Grade 3 infusion‑related symptom at the subsequent infusion.

If a planned dose of DARZALEX is missed, the dose should be administered as soon as possible and the dosing schedule should be adjusted accordingly, maintaining the treatment interval.

Dose modifications

No dose reductions of DARZALEX are recommended. Dose delay may be required to allow recovery of blood cell counts in the event of haematological toxicity(see section4.4).For information concerning medicinal products given in combination with DARZALEX, see corresponding Summary of Product Characteristics.

Recommended concomitant medications

Pre‑infusion medication

Pre‑infusion medications should be administered to reduce the risk of IRRs to all patients approximately 1-3 hours prior to every infusion of DARZALEX as follows:

·Corticosteroid (long-acting or intermediate-acting)

Monotherapy:

Methylprednisolone 100 mg, or equivalent, administered intravenously. Following the second infusion, the dose of corticosteroid may be reduced (oral or intravenous methylprednisolone 60 mg).

Following the second infusion, the dose of intravenous corticosteroid may be reduced (methylprednisolone 60 mg) at the discretion of the physician.

Post‑infusion medication

Post-infusion medications should be administered to reduce the risk of delayed infusion‑related reactions as follows:

Monotherapy:

For the prevention of delayed IRRs, oOral corticosteroid (20 mg methylprednisolone or equivalent dose of an intermediate‑acting or long‑acting corticosteroid in accordance with local standards) should be administered on each of the two days following all infusions (beginning the day after the infusion).

Combination therapy:

Consider administering low-dose oral methylprednisolone (≤20mg) or equivalent the day after the DARZALEX infusion.However, if a background regimen-specific corticosteroid (e.g. dexamethasone) is administered the day after the DARZALEX infusion, additional post-infusion medications may not be needed (see section5.1).

Additionally, for patients with a history of chronic obstructive pulmonary disorderdisease, the use of post‑infusion medications including short and long acting bronchodilators, and inhaled corticosteroids should be considered. Following the first four infusions, if the patient experiences no major IRRs, these inhaled post‑infusion medications may be discontinued at the discretion of the physician.

Prophylaxis for herpes zoster virus reactivation

Anti‑viral prophylaxis should be considered for the prevention of herpes zoster virus reactivation.

Special populations

Renal impairment

No formal studies of daratumumab in patients with renal impairment have been conducted. Based on a population pharmacokinetic (PK) analysis analyses no dosage adjustment is necessary for patients with renal impairment (see section 5.2).

Hepatic impairment

No formal studies of daratumumab in patients with hepatic impairment have been conducted.

Based ona population PK analyseis, no dosage adjustments are necessary for patients with mild hepatic impairment (Total Bilirubin [TB] 1.0 x to 1.5 x upper limit of normal [ULN] or aspartate aminotransferase [AST] > ULN). Daratumumab has not been studied in patients with moderate to severe hepatic impairment (TB > 1.5 x ULN and any AST), therefore no dose recommendations can be made in these patient populations (see section 5.2).

4.4 Special warnings and precautions for use

Infusion‑related reactions

Infusion‑related reactions (IRRs) were reported in approximately half of all patients treated with DARZALEX. Monitor such patients throughout the infusion and the post‑infusion period.

The majority (95%) of IRRs occurred at the first infusion. Five Four percent of all patients had an IRR at more than one infusion. Severe reactions have occurred, including bronchospasm, hypoxia, dyspnoea, hypertension, laryngeal oedema and pulmonary oedema.Symptoms predominantly included (≥ 5%) nasal congestion, chills, cough, allergic rhinitis, throat irritation, dyspnoea, chills, vomiting and nausea, and were mild to moderate in severity. Less common symptoms were wheezing, allergic rhinitis, pyrexia, chest discomfort, pruritus and hypotension Severe IRRs (3%) including bronchospasm (1.3%), hypertension (0.6%), and hypoxia (0.6%) were also reported (see section 4.8).

Patients should be pre‑medicated with antihistamines, antipyretics and corticosteroids to reduce the risk of IRRs prior to treatment with DARZALEX. DARZALEX infusion should be interrupted for IRRs of any severity. Medical management/supportive treatment for IRRs should be instituted as needed. The infusion rate should be reduced when re‑starting the infusion (see section 4.2).

For the preventionTo reduce the risk of delayed IRRs, oral corticosteroids should be administered to all patients following DARZALEX infusions.the first and second day after all infusions. Additionally the use of post‑infusion medications (e.g. inhaled corticosteroids, short and long acting bronchodilators) should be considered for patients with a history of chronic obstructive pulmonary disorder disease to manage respiratory complications should they occur (see section 4.2).

DARZALEX therapy should be permanently discontinued in the event of life‑threatening IRRs.

Monitor complete blood cell counts periodically during treatment according to manufacturer’s prescribing information for background therapies. Monitor patients with neutropenia for signs of infection. DARZALEX delay may be required to allow recovery of blood cell counts. No dose reduction of DARZALEX is recommended. Consider supportive care with transfusions or growth factors.

4.5 Interaction with other medicinal products and other forms of interaction

Clinical pharmacokinetic assessments of pomalidomide, thalidomide, and bortezomib indicated no clinically-relevant drug-drug interaction between DARZALEX and these combination therapies.

4.8 Undesirable effects

Summary of the safety profile

The safety data described below reflects exposure to DARZALEX (16mg/kg) in 820patients with multiple myeloma including 526patients from two PhaseIII active-controlled trials who received DARZALEX in combination with either lenalidomide (DRd; n=283; Study MMY3003) or bortezomib (DVd; n=243; Study MMY3004) and five open-label, clinical trials in which patients received DARZALEX either in combination with pomalidomide (DPd; n=103), in combination with lenalidomide (n=35) or as monotherapy (n=156).

Table 3 4summariszes the adverse drug reactions that occurred in patients receiving DARZALEX.The data reflect exposure to DARZALEX in three pooled open‑label, clinical studies that included 156 patients with relapsed and refractory multiple myeloma treated with DARZALEX at 16 mg/kg. The median duration of DARZALEX treatment was 3.3 months, with the longest duration of treatment being 20 months.

Adverse event table revised

Infusion‑related reactions

In clinical trials (monotherapy and combination treatments; N=820) the incidence of any grade infusion‑related reactions was 46% with the first infusion of DARZALEX, 2% with the second infusion, and 3% with subsequent infusions. Less than 1% of patients had a Grade3 infusion‑related reaction with second or subsequent infusions.

The median time to onset of a reaction was 1.4hours (range: 0.02 to 72.8hours). The incidence of infusion interruptions due to reactions was 42%. Median durations of infusion for the 1st, 2nd and subsequent infusions were 7, 4.3 and 3.5hours respectively.

The median time to onset of a reaction was 1.5hours (range: 0.02 to 9.3hours). Median durations of infusion for the first, second and subsequent infusions were 7.0, 4.6 and 3.4hours respectively.

Infections

In patients receiving DARZALEX combination therapy, Grade3 or 4 infections were reported with DARZALEX combinations and background therapies (DVd: 21%, Vd: 19%; DRd: 27%, Rd: 23%; DPd: 28%). Pneumonia was the most commonly reported severe (Grade3 or 4) infection across studies. Discontinuations from treatment were reported in 2% to 5% of patients. Fatal infections were reported in 0.8% to 2% of patients across studies, primarily due to pneumonia and sepsis.

5.1 Pharmacodynamic properties ~significant updates

5.2 Pharmacokinetic properties ~significant updates

Updated on 3 May 2017 PIL

Reasons for updating

Change to section 4.1 - Therapeutic indications

Change to section 4.2 - Posology and method of administration

Change to section 4.4 - Special warnings and precautions for use

Change to section 4.5 - Interaction with other medicinal products and other forms of interaction

Change to section 4.8 - Undesirable effects

Change to section 5.1 - Pharmacodynamic properties

Change to section 5.2 - Pharmacokinetic properties

Change to section 10 - Date of revision of the text

Free text change information supplied by the pharmaceutical company

4.1 Therapeutic indications

DARZALEX is indicated:

·as monotherapy is indicated for the treatment of adult patients with relapsed and refractory multiple myeloma, whose prior therapy included a proteasome inhibitor and an immunomodulatory agent and who have demonstrated disease progression on the last therapy.

·in combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone,for the treatment of adult patients with multiple myeloma who have received at least one prior therapy

4.2 Posology and method of administration

Dose

Standard dosing for monotherapy and in combination with lenalidomide (4‑week cycle regimen):

The recommended dose is DARZALEX 16 mg/kg body weight administered as an intravenous infusion according to the following dosing schedule in Table1.:

For dose and schedule of medicinal products administeredwith DARZALEX, see section5.1 and the corresponding Summary of Product Characteristics.

Infusion rates

Following dilution the DARZALEX infusion should be intravenously administered at the appropriate initial infusion rate, as presented in Table 2 3 below. Incremental escalation of the infusion rate should be considered only if the previous infusion of daratumumab was well‑toleratedin the absence of infusion reactions. as defined in Table 2.

Table 32: Infusion rates for DARZALEX administration

Dilution volume

Initial infusion rate (first hour)

Increments of infusion ratea

Maximum infusion rate

First infusion

1,000 mL

50 mL/hour

50 mL/hour every hour

200 mL/hour

Second infusionainfusionb

500 mL

50 mL/hour

50 mL/hour every hour

200 mL/hour

Subsequent infusionsbinfusionsc

500 mL

100 mL/hour

50 mL/hour every hour

200 mL/hour

aIncremental escalation of the infusion rate should be considered only in the absence of infusion reactions.

abA dilution volume of 500mL should be used only if there were no ≥ Grade 1 IRRs during the first 3 hours of the first infusion. Otherwise, continue to use a dilution volume of 1000mL and instructions for the first infusion.Modified rates should only be used if the first infusion of DARZALEX was well‑tolerated as defined by an absence of ≥ Grade 1 IRRs during the first 3 hours.

bcA modified initial rate for subsequent infusions (i.e. third infusion onwards) should only be used only if there were no ≥ Grade 1 IRRs during a final infusion rate of ≥ 100 mL/hr in the first two infusions. Otherwise, use instructions for the second infusionModified rates should only be used if the first 2 infusions of DARZALEX were well‑tolerated as defined by an absence of ≥ Grade 1 IRRs during a final infusion rate of ≥ 100 mL/hr.

Management of infusion‑related reactions

Management of IRRs may further require reduction in the rate of infusion, or treatment discontinuation of DARZALEX as outlined below (see section 4.4).

·Grade 1‑2 (mild to moderate): Once the patient’s condition is stablereaction symptoms resolve, the infusion should be resumed at no more than half the rate at which the IRR occurred. If the patient does not experience any further IRR symptoms, infusion rate escalation may be resumed at increments and intervals as clinically appropriate up to the maximum rate of 200mL/hour (Table 23).

·Grade 3 (severe): If the intensity of the IRR decreases to Grade 2 or lowerOnce reaction symptoms resolve, restarting of the infusion may be considered at no more than half the rate at which the reaction occurred. If the patient does not experience additional symptoms, infusion rate escalation may be resumed at increments and intervals as appropriate (Table 32). The procedure above should be repeated in the event of recurrence of Grade 3 symptoms. Permanently discontinue DARZALEXupon the third occurrence of a Grade 3 or greater infusion reaction if the patient experiences a ≥ Grade 3 infusion‑related symptom at the subsequent infusion.

If a planned dose of DARZALEX is missed, the dose should be administered as soon as possible and the dosing schedule should be adjusted accordingly, maintaining the treatment interval.

Dose modifications

No dose reductions of DARZALEX are recommended. Dose delay may be required to allow recovery of blood cell counts in the event of haematological toxicity(see section4.4).For information concerning medicinal products given in combination with DARZALEX, see corresponding Summary of Product Characteristics.

Recommended concomitant medications

Pre‑infusion medication

Pre‑infusion medications should be administered to reduce the risk of IRRs to all patients approximately 1-3 hours prior to every infusion of DARZALEX as follows:

·Corticosteroid (long-acting or intermediate-acting)

Monotherapy:

Methylprednisolone 100 mg, or equivalent, administered intravenously. Following the second infusion, the dose of corticosteroid may be reduced (oral or intravenous methylprednisolone 60 mg).

Following the second infusion, the dose of intravenous corticosteroid may be reduced (methylprednisolone 60 mg) at the discretion of the physician.

Post‑infusion medication

Post-infusion medications should be administered to reduce the risk of delayed infusion‑related reactions as follows:

Monotherapy:

For the prevention of delayed IRRs, oOral corticosteroid (20 mg methylprednisolone or equivalent dose of an intermediate‑acting or long‑acting corticosteroid in accordance with local standards) should be administered on each of the two days following all infusions (beginning the day after the infusion).

Combination therapy:

Consider administering low-dose oral methylprednisolone (≤20mg) or equivalent the day after the DARZALEX infusion.However, if a background regimen-specific corticosteroid (e.g. dexamethasone) is administered the day after the DARZALEX infusion, additional post-infusion medications may not be needed (see section